Conformational dynamics of a nicotinic receptor neurotransmitter site

This article has 17 evaluations Published on
Read the full article Related papers
This article on Sciety

Abstract

Agonists increase receptor activity by providing net-favorable binding energy to active versus resting conformations of their target sites. We used molecular dynamics (MD) simulations to explore dynamics of the low-to-high affinity conformational change (L→H) at theTorpedoα–δ nicotinic acetylcholine receptor neurotransmitter site, using 4 agonists. Alternative conformations were identified in trajectories generated from a single starting structure by matching approximate binding energies calculatedin silicowith exact values measured experimentallyin vitro. In all simulations, the L→H transition started with a rotation of the agonist about its cationic center (’flip’), followed by a staged downward displacement of loop C (’flop’) and the formation of a compact, hydrophobic and stable high-affinity pocket (’fix’). Agonist rotation and a transient intermediate state are only in simulations but can be confirmed or refuted, for example by time-resolved structures.

Related articles

Related articles are currently not available for this article.